The major goal of this project was to examine the roles of glial cells in inflammation-related neurodegeneration. We have employed both in vitro and in vivo rodent models of Parkinson's disease by focusing our studies on the mesencephalic dopaminergic neurons. Our laboratory was among the first to report that lipopolysaccharide (LPS)-induced neurotoxicity depended on the presence of glial cells. These cells secrete a variety of proinflammatory factors, including cytokines, free radicals and arachidonate metabolites that are the main contributors to the pathogenesis of inflammation-related neurodegenerative diseases. Recent studies from our laboratory indicate that microglia mediate a variety of environmental (such as rotenone, paraquat) or endogenous (such as amyloid protein, prion) neurotoxin-induced neurotoxicty, which were originally thought to produce neuronal damge by exerting directs effect on neurons. These findings have important implications in the research field of neurodegenerative diseases since our data suggest that microglia, instead of neurons, are the main target of these neurotoxins. Our current efforts focus on determining the relative importance of these proinflammatory factors in glia-mediated neuronal damage.